Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-kappaB and initiates tumour vascular normalization.
Targeting a unique EGFR epitope with monoclonal antibody 806 activates NF-kappaB and initiates tumour vascular normalization.
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DOI：
10.1111/j.1582-4934.2009.00783.x
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发表时间：
2009-09
影响因子：
5.3
通讯作者：
Johns TG
中科院分区：
文献类型：
--
作者：
Gan HK;Lappas M;Cao DX;Cvrljevdic A;Scott AM;Johns TG
靶向表皮生长因子受体（EGFR）的单克隆抗体（mAb）和酪氨酸激酶抑制剂（EGFR通常在上皮恶性肿瘤和神经胶质瘤中病理性地过表达或突变）已经取得了一定的成功，其中一些被批准用于人类使用。MAb 806是针对de 2 - 7 EGFR（或EGFRvIII）提出的，de 2 - 7 EGFR是一种在神经胶质瘤中表达的组成型活性突变，但当野生型（wt）EGFR被自分泌环、过表达或突变激活时，它也识别野生型（wt）EGFR的一个子集（<10%）。它不结合正常组织如肝脏中的无活性EGFR。用mAb 806处理的表达de 2 - 7 EGFR的胶质瘤异种移植物显示出受体自磷酸化减少、p27 KIP 1增加和细胞增殖减少。表达通过过表达或自分泌配体激活的wtEGFR的异种移植物也被mAb 806抑制，但抑制机制难以阐明，特别是因为mAb 806在体外不阻止wtEGFR磷酸化或下游信号传导。因此，我们检查了mAb 806对A431异种移植物血管生成的作用。MA B 806通过激活NF-κB增加血管内皮生长因子（VEGF）和白细胞介素-8的产生，并使肿瘤血管系统正常化。NF-κB的药理学抑制完全消除了mAb 806的活性，表明NF-κB活化对其在异种移植物中的抗肿瘤功能是必需的。考虑到VEGF的增加，我们将mAb 806与贝伐单抗在体内组合，导致相加活性。
Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), which is often pathogenetically overexpressed or mutated in epithelial malignancies and glioma, have been modestly successful, with some approved for human use. MAb 806 was raised against de2–7EGFR (or EGFRvIII), a constitutively active mutation expressed in gliomas, but also recognizes a subset (<10%) of wild-type (wt) EGFR when it is activated by autocrine loop, overexpression or mutation. It does not bind inactive EGFR in normal tissues like liver. Glioma xenografts expressing the de2–7EGFR treated with mAb 806 show reduced receptor autophosphorylation, increased p27KIP1 and reduced cell proliferation. Xenografts expressing the wtEGFR activated by overexpression or autocrine ligand are also inhibited by mAb 806, but the mechanism of inhibition has been difficult to elucidate, especially because mAb 806 does not prevent wtEGFR phosphorylation or downstream signalling in vitro. Thus, we examined the effects of mAb 806 on A431 xenograft angiogenesis. MAb 806 increases vascular endothelial growth factor (VEGF) and interleukin-8 production by activating NF-κB and normalizes tumour vasculature. Pharmacological inhibition of NF-κB completely abrogated mAb 806 activity, demonstrating that NF-κB activation is necessary for its anti-tumour function in xenografts. Given the increase in VEGF, we combined mAb 806 with bevacizumab in vivo, resulting in additive activity.